TR201809003T4 - Therapeutic agent for motor disorders. - Google Patents

Abstract

The agent for the treatment and / or prophylaxis of a movement disorder, the agent for the treatment and / or prophylaxis of movement disorder is extrapyramidal syndrome, the agent for treatment and / or prophylaxis of the movement disorder, bradykinesia, gait disorder, dystonia, dyskinesia or late dyskinesia, The agent is provided for treatment and / or prophylaxis wherein treatment of DOPA and / or dopamine agonist and the like is a side effect, wherein R 1 represents aryl and the like as an active ingredient, and A thiazole derivative thereof or a pharmaceutically acceptable salt thereof.

Description

DESCRIPTION THERAPEUTIC SUBSTANCE FOR ENGINE DISORDERS Explanation Technical Area This invention is specific for use in the treatment and/or prophylaxis of a movement disorder. is related to the substance, where the movement disorder is L-DOPA and/or dopamine agonist end-of-dose phenomenon and on-off (good-bad) fluctuation upon administration of It is a motor complication selected among

Known Issues Parkinson's disease is associated with tremor, bradykinesia, difficulty walking and coordinated movement, and so on. It is a characteristic brain disease. This disease is a disease that manages the muscle movements of the brain. associated with the damage. Often, the first symptom of Parkinson's disease, especially the Body A tremor of an arm or leg while standing still. Tremors often begin in one half of the body and it often happens in one of the hands. Other common symptoms include slow movement (bradykinesia), inability to move (akinesia), stiffness in the body and arms and legs, shuffling and hunched posture and so on. Parkinson's patients have less facial expressions and a soft voice. They tend to talk. Parkinson's disease depression, anxiety, personality change, cognitive disorders, such as dementia, sleep disorders, speech disorders, or sexual dysfunction may cause secondary symptoms. Parkinson's disease currently used clinically drug therapy mainly controls the imbalance between neurotransmitters. It controls Parkinson's symptoms by taking it under Patients with early-stage Parkinson's are often responds well to symptomatic treatment with a dopamine replacement therapy; but your disease Disability increases with progression.

Currently used drugs for Parkinson's disease usually provide adequate symptomatic control for years. motor fluctuations, which impair clinical response in many patients, and dyskinesias occur (The New England Journal of Medicine (N. Eng. J. Med.), vol. 342, More than thirty years have passed since the discovery of L-DOPA, but L-DOPA still remains for Parkinson's disease. It is the best substance for the treatment of disease. In the early stages of Parkinson's disease, patients they generally respond well to L-DOPA. However, as the disease progresses, the benefit of L-DOPA shows a decreasing trend. This is not because L-DOPA has lost its effectiveness, for example motor complications such as worsening of the motor or adverse fluctuations in motor response. is the output. his "on" state ("good" state) in which he is relatively free from symptoms an inexorably lost state and a state with Parkinson's (“oft” state) emerges. is an event. This is the case when Parkinson's patients receive L-DOPA therapy and demonstrate its efficacy. It occurs when exposed to a sufficient amount of L-DOPA for However, these symptoms However, the effect of treatment may reappear suddenly. effect of L-DOPA7 in patients with Parkinson's despite exposure to a small amount of L-DOPA7. It is a phenomenon of decreasing duration. The peculiarity of this phenomenon is that the "off" state gradually reoccurs. is the emergence and shortening of the “on” state. That is, the duration of the treatment effect of L-DOPA a gradual shortening (the duration of the treatment effect is shortened after L-DOPA administration) This indicates the phenomenon of disease in Parkinson's patients treated with L-DOPA. clearly seen in an advanced stage.

Dyskinesia with general chorea-like symptoms (hyperactive, aimless dance-like movement) and dystonia (prolonged, abnormal muscle contraction). In 1974, Duvoisin first focused on these abnormal involuntary movements, and in half of Parkinson's patients or found that more of them had dyskinesia within 6 months of treatment. Treatment time The longer it gets, the higher the frequency and severity of dyskinesia. Possible in Parkinson's disease in a study of the potential benefits of neuroprotectors - the DATATOP study -, In 20-30% of patients treated with L-DOPA for an average of 20.5 months, L-DOPA-induced dyskinesia was observed. Eventually, most patients treated with L-DOPA experienced dyskinesia; 5 Dyskinesia developed in up to 80% of the patients during the year. (Annals of Neurology (Ann.

Neurol.), vol. 39, p. 37 (1966); The New England Journal of Medicine (N. Eng. J. Med), agonists are sufficient for hypersensitive dopamine receptors in the putamen of the brain. concentration (peak dose dyskinesia). However, dyskinesia dopamine when the concentration is low (off-dystonia) or when the dopamine concentration is elevated or decrease (biphasic dyskinesia). On the other hand, adenosine is distributed throughout the body and is centrally located via its receptors. Various physiological effects on nervous system, heart muscle, kidneys, smooth muscle and the like (see non-patent document 1) and an antagonist of various diseases It is known to be useful for treatment and/or prophylaxis. For example, adenosine A1 antagonists are known to facilitate defecation (The Japanese Journal of Pharmacology (Jpn. J. Pharmacol.), Vol. 68, p. 119 (1995)). Moreover It is known that adenosine AZA receptors play a role especially in the central nervous system. and antagonists of adenosine A2A receptors, for example for Parkinson's disease and the like therapeutic drugs (see non-patent document 2), therapeutic drugs for sleep disorder (see Nature Neuroscience, p. 858 (2005); as patent document 1) and so on. It is known to be useful. The relationship between adenosine receptors and Parkinson's disease There are many reports on the subject (see, for example: non-patent document 3 and 4).

In addition, by using an adenosine AgA receptor antagonist, (i) L-DOPA is a side-effect of treatment. (ii) L-DOPA dose in the treatment of L-DOPA (iii) Parkinson's disease in the treatment of L-DOPA a method of prolonging the efficacy of treatment, (iv) reducing a movement disorder, etc. A method is known to treat it (see patent document 2). to be specific if necessary, tremor, bradykinesia, gait disturbance, akinesia, and so on. An adenosine represented by formula (A) in patients with Parkinson's disease It is known that it can be suppressed by administering AZA receptor antagonist and L-DOPA and (A) adenosine AZA receptor antagonist L-DOPA et al. It suppresses dyskinesia that occurs with its application. Also, represented by formula (A) an adenosine A2A receptor antagonist, L-DOPA in MPTP-treated marmoset and/or when used in combination with a dopamine agonist, it has an anti-Parkinsonian effect. (see non-patent document 5.6), may cause dyskinesia (non-patent document 5.6) see document 6) and does not cause dyskinesia, but potentiates the effect against Parkinson's (see non-patent document 7°). On the other hand, compounds represented by, for example, formula (IA), (IB), (IC), (ID), etc. It has affinity for adenosine A2A receptors and has a therapeutic effect for Parkinson's disease. (see patent document 3). Also, the adenosine A2A receptor Thiazole derivatives with antagonistic activity are known (see patent document 49). This a substance (patent certificate) for the treatment and/or prophylaxis of sleep disorder 1”), a substance for the treatment and/or prophylaxis of migraine (see patent 5”), useful as an analgesic tolerance inhibitor (see patent 63), and the like is also known. patent document 7 of A2a receptor function, including neurodegenerative diseases Substituted 2-aminothiazole derivatives useful in the treatment of diseases mediated by is explained. Patent document 8, with A221 receptor ligands and treatment of neurological and psychiatric diseases Compounds useful in the treatment of the disease are described. patent document 93da, adenosine AZa receptor for use in the treatment of movement disorders related to its antagonists. for use in the prevention and/or treatment of movement disorders thiazolopyrimidine derivatives with an adenosine A2a receptor antagonistic effect is explained. patent document 11 on CNS (central nervous system) diseases such as Parkinson's disease Specific compounds are disclosed for use in the treatment of in non-patent document 8, the adenosine A2a antagonist KW 60023 with L-DOPA or selective Combined use with Dl or D2 dopamine agonists treated with MPTP increased activity against Parkinson's in monkeys, but decreased activity against dyskinesia. It is explained that it does not increase. non-patent document 9 of the adenosine A2a receptor antagonist istradephylline (KW-6002) It is explained that it reduces the “off” time in Parkinson's disease. unilateral 6-OHDA of the new adenosine A2a antagonist ST1535 in non-patent document 10 L-DOPA is described to potentiate the effects of a threshold dose in rats with lesion. non-patent document 1 in 1 of the adenosine A2a receptor antagonist 8-(3-chlorostyryl) caffeine The effect on L-DOPA biotransformation in the rat striatum is described. in non-patent document 12, SCH 58261, an A2a adenosine receptor antagonist, non-patent document 13 A threshold of L-DOPA in MPTP-treated marmots It is related to the adenosine A2a receptor antagonist ST1535°, which potentiates the effects of the dose. 63, no. 3, pages 295-302 CHICHESTER, GB, vol. 41, no. 2, pages 160-171 PHARMACOLOGY, ELSEVIER SCIENCE, NL, vol. 546, no. 1-3, pages 82-87 Summary of the Invention Problems to be Solved with Invention One object of this invention is the treatment and/or prophylaxis of specific movement disorders. to provide a substance for use.

Ways to Solve Problems This invention relates to (1) - (12)” below. (1) Formula for use in the treatment and/or prophylaxis of a movement disorder The thiazole derivative represented by (IC) or a pharmaceutically acceptable salt thereof, wherein movement disorder, L- End-of-dose phenomenon upon administration of DOPA and/or dopamine agonist therapy and on-off ripple. (2) the thiazole derivative according to (1) or a pharmaceutically acceptable salt thereof; where motor complication is the end-of-dose phenomenon. (3) the thiazole derivative according to (1) or a pharmaceutically acceptable salt thereof, where the motor complication is the on-off surge. (4) Formula (lC) for use in suppressing or reducing a movement disorder The thiazole derivative represented by @"11th or a pharmaceutically acceptable salt thereof, wherein movement disorder, L- End-of-dose phenomenon upon administration of DOPA and/or dopamine agonist therapy and on-off ripple. (5) the thiazole derivative according to (4) or a pharmaceutically acceptable salt thereof; where motor complication is the end-of-dose phenomenon. (6) the thiazole derivative according to (4) or a pharmaceutically acceptable salt thereof; where the motor complication is the on-off surge. (7) A thiazole derivative represented by formula (IC) or a pharmaceutically acceptable salt thereof for the treatment of a movement disorder and/or its use for the manufacture of a substance for prophylaxis, wherein movement disorder, End-of-dose seen upon administration of L-DOPA and/or dopamine agonist therapy It is a motor complication selected from the phenomenon of on-off fluctuation. (8) Use according to (7)*, where motor complication is the end-of-dose phenomenon. (9) is the usage according to (7)7, where the motor complication is on-off surge. (10) A thiazole derivative represented by formula (IC) or a pharmaceutically acceptable salt thereof, a movement disorder for the manufacture of a substance intended to suppress or reduce movement disorder, on administration of L-DOPA and/or dopamine agonist therapy A motor selected from the end-of-dose phenomenon and on-off ripple seen is a complication. (11) is the use according to (10), where the motor complication is the end-of-dose phenomenon. (12) is the use according to (10), where the motor complication is on-off surge.

Here also the following is described: An agent for the treatment and/or prophylaxis of a movement disorder a thiazole derivative represented by formula (I) or its pharmaceutically acceptable contains a salt that can be: R2 i s>~ 'gi-R1 where R1 is aryl, aralkyl, an aromatic heterocyclic group, aromatic heterocycle-alkyl, represents aliphaticheterocycle-alkyl or tetrahydropyranyloxy, each optional as halogen; low, optionally substituted with lower alkoxy or morpholino alkyl; lower alkoxy; lower alkanoyl; and 1 to 3 substituents selected from the group consisting of Vinyl is substituted and R2 represents pyridyl or tetrahydropyranyl.

Impact of the Invention The present invention is used in the treatment and/or treatment of a movement disorder as described above. A thiazole represented by formula (IC) as an active ingredient for use in prophylaxis a substance comprising a derivative or a pharmaceutically acceptable salt thereof; (a) formula (IC) or a pharmaceutically acceptable derivative thereof. salt and (b) L-DOPA and/or a dopamine agonist; (a) a thiazole derivative represented by formula (IC) or its pharmaceutically acceptable a first component containing a salt thereof; and (b) a second component containing L-DOPA and/or a dopamine agonist. provides a kit containing the component and the like. Brief Description of Drawings In Figure 1, the effect of compound (1C) on the disability score in Test Sample 3 is shown. The vertical axis represents the disability score and the horizontal axis It shows the time (minutes) after the application. It's a solvent and L-DOPA indicates the combination of a compound (IC) and L-DOPA. shows.

The maximum effect in Test Example 3 of the compound (IC) in Figure 2 (minimum physical disability) The effect on the score) is shown. The vertical axis represents the minimum physical disability score. and the horizontal axis shows the L-DOPA dosage. It combines a solvent and L-DOPA. and it represents a combination of a compound (IC) and L-DOPA.

Format of the Invention Application movement disorder, loss of movement, extrapyramidal syndrome, or similar motor control impairment, hyperactivity (eg, dystonia, dyskinesia, tardive dyskinesia, tremor, chorea, balismus, akathisia, athetosis, bradykinesia, gait disturbance, freezing, rigidity, posture imbalance, muscle twitching, tics or Tourette's syndrome, postural reflex disorder or is a neurological disorder characterized by such) or similar.

In the article of this invention for the treatment and/or prophylaxis of a movement disorder, movement disorder is the movement disorder mentioned above and includes the end-of-dose phenomenon and pre- Indicates motor complications selected from the off surge.

Although L-DOPA provides powerful and rapid therapeutic benefits in Parkinson's disease, end-of-dose phenomenon, on-off ripple, dyskinesia, and so on. severe and uncomfortable adverse reactions, including complications (Marsden et al., “Fluctuations in disability in Parkinson's disease: clinical aspects” In: Marsden, CD, Fahn S., editors. Movement disorders. New York: Butterworth Scientific, pp. 96-122 (1982)). Nausea from a single L-DOPA administration, It is also known to cause side effects such as vomiting, anorexia and so on.

A dopamine agonist can also cause dyskinesia. Use of a dopamine agonist neuropsychiatric side effects are often irritating, especially hallucinations and psychosis.

Advantages when used as an adjunct to therapy with a dopamine agonist L-DOPA However, as mentioned above, the engine caused by L-DOPA with it complications are extremely difficult or even impossible to control (Olanow, Watts, and Kollereds. An Algorithm (Decision Tree) for the Management of Parkinson's Disease: Treatment Guidelines, Neurology 56, Supplement 5 (2001). Also, excessive daytime sleepiness associated with Parkinson's disease It has been reported that sleepiness can be increased by L-DOPA and/or a dopamine agonist. (Neurology, vol. 67, p. 853 (2006)).

In this invention, the side effects of L-DOPA and/or dopamine agonist therapy are L-DOPA and/or a In the treatment of Parkinson's disease and similar in which dopamine agonist is used and/or refers to the above-mentioned side effects that occur in prophylaxis. Among them motor complications such as the end-of-dose phenomenon and the on-off fluctuation.

That is, the article of this invention for the treatment and/or prophylaxis of a motion sickness, A side effect on the administration of L-DOPA and/or a dopamine agonist, Especially a motor complication such as end-of-dose phenomenon and on-off fluctuation can be reduced or suppressed.

As Parkinson's disease progresses, more dopamine cells die and the rest of the cells are L- adequate dopamine to maintain benefits in DOPA and/or dopamine agonist therapy. cannot store. As a result, the duration of action decreases with each dose and the patient becomes more or more frequent. Needs dosing. After 2-5 years, 50-75% of patients are given L-DOPA. There will be fluctuations in the response, for example in the length of the “on” period and so on. with ripples end-of-dose phenomenon associated with fluctuations in duration of action, on-off fluctuations, dyskinesia (involuntary movement), or the like. Therefore, such side effects L-DOPA and/or dopamine agonist therapy due to the initiation of etc. It can be difficult to sustain. Therefore, the application of this invention to the treatment of a movement disorder and/or prophylaxis by reducing the above-mentioned side effects or by preventing the effective duration of treatment with L-DOPA and/or a dopamine agonist. can be extended. Specifically, this invention is intended for the treatment of a movement disorder and/or The substance for prophylaxis of patients with advanced Parkinson's disease is L- Effectively avoiding the end-of-dose phenomenon or similar that creates problems in DOPA therapy. can prevent.

L-DOPA used for the treatment of the above-mentioned L-DOPA and/or dopamine agonist is a L-DOPA or a salt, hydrate or prodrug thereof, or the like, as the active ingredient and examples thereof include compositions containing them as an active ingredient, and the like. takes place. Examples of commercially available products include Menesit (registered trademark), EC Doparl (registered trademark), Doparl (registered trademark), Madopar (registered trademark), and similar place. Dopamine agonist as an active ingredient a dopamine agonist or its may include a salt, hydrate, prodrug or the like, examples of which include an active pramipexole, talipexole, ropinirole, cabergoline, pergolite or the like, or a compositions containing the hydrochloride, mesylate or prodrug thereof, or the like, and the like.

Examples of commercially available products include Domin (registered trademark), Permax (registered trademark). trademark), Cabaser (registered trademark), and the like.

The substance of the present invention is typically a thiazole derivative represented by formula (IC) or its a pharmaceutically acceptable salt and L-DOPA and/or a dopamine agonist. in combination and can reduce every symptom of Parkinson's disease or L-DOPA and/or a dopamine agonist mentioned above can inhibit side effects (eg end-of-dose phenomenon, on-off fluctuation, dyskinesia or similar) or suppress symptoms.

Below, the compound represented by formula (1) is referred to as Compound (1). another formula Compounds with numbers pass in the same way.

The definition of each group in formula (I) is as follows.

Examples of the lower alkyl, lower alkoxy, and lower alkyl part of the lower alkanoyl range from 1 to straight or branched alkyl with carbon atoms, and more specific examples of this include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, noni1,decyl and the like.

Examples of aralkyl include aralkyl having 7 to 16 carbon atoms, and more specifically examples include benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, phenylheptyl, phenyloctyl, phenylnonyl, phenyldecyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl, anthrylmethyl, anthrilethyl and the like.

Examples of aryl include aryl having 6 to 14 carbon atoms, and more specific examples include phenyl, naphthyl, azulenyl, anthryl and the like.

Examples of aromatic heterocyclic group include a nitrogen atom, an oxygen atom, and a a 5-membered or 6-membered monocyclic containing at least one atom selected from sulfur atom aromatic heterocyclic group, 3 to 8 membered rings fused, one nitrogen atom, one oxygen a bicyclic or tricyclic, having at least one atom selected from atom and one sulfur atom fused aromatic heterocyclic group and the like. More specific examples include furil, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, isoindolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, b]pyridyl, 7,8-dihydro-SH-thiopyrano[4,3-b]pyridyl, and the like.

Examples of aromatic heterocycle-alkyl include an aromatic heterocyclic group attached to the alkylene. There is a group where Aromatic heterocyclic group includes those exemplified in the heterocyclic group and alkylene an alkylene having 1 to 10 carbon atoms. and specific examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene and the like takes place. Specific examples of aromatic heterocycle-alkyl include pyrrolylmethyl, pyrrolylethyl, thiazolylmethyl, pyridylmethyl, pyridylethyl, pyrimidinylmethyl, pyrimidinylethyl, indolylmethyl, benzimidazolylmethyl and the like.

Examples of aliphatic heterocycle-alkyl include where the aliphatic heterocyclic group is attached to the alkylene. there is a group. Examples of aliphatic heterocyclic group include a nitrogen atom, an oxygen A 5-membered or 6-membered atom containing at least one atom selected from atom and one sulfur atom. monocyclic aliphatic heterocyclic group, a nitrogen atom, an oxygen atom, and a sulfur atom a fused cycle of 3 to 8 membered rings having at least one atom selected from, or tricyclic fused aliphatic heterocyclic group. More specific examples include aziriiiiil, azetidinyl, pyrrolidinyl, piperidino, piperidinyl, azepanil, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl, tetrahydrofuranyl, tetrahydro- 2H-pyranyl, 5,6-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyridyl, oxazolidinyl, morpholino, morpholinyl, thioxazolidinyl, thiomorpholinyl, 2H-oxazolyl1, 2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzodioxolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydro-ZH- chromanyl, dihydro-1H-chromanyl, dihydro-2H-thiochromanyl, dihydro-1H-thiochromanyl, tetrahydroquinoxalinyl, tetrahydroquinazolinyl, dihydrobenzodioxanyl, and the like.

Examples of alkylene include alkylene having 1 to 10 carbon atoms, and specific examples methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene and the like. Aliphatic heterocycle Examples of alkyl include 5,6-dihydro-2H-pyridylmethyl, 5,6-dihydro-2H-pyridylethyl, tetrahydro- 2H-pyranylmethyl, 5,6-dihydro-2H-pyranylmethyl1, 5,6-dihydro-2H-pyranylethyl, morpholinomethyl, morpholinoethyl, piperazinylmethyl, oxazolidinylmethyl and the like.

Halogen refers to each fluorine, chlorine, bromine and iodine atom.

Compound (1) or a pharmaceutically acceptable salt thereof various subtypes of adenosine receptors (eg adenosine A1, AZA, A213 and A3 receptors), preferably It has a potent antagonistic activity against adenosine A2A receptors selected from among is a compound.

Thus, Compound (I) or a pharmaceutically acceptable salt thereof preferably a compound with strong affinity for adenosine AZA receptors. For example, compound In the adenosine AZA receptor binding test shown in Test Example 1, below 50% or more inhibitor, preferably at a test compound concentration of 3><10`8 mol/L a compound with activity, more preferably 50% at a test compound concentration of 1><10`8 mol/L or a compound with more inhibitory activity, more preferably 3X 10'9 mol/L test compound A compound with 50% or more inhibitory activity at concentration 50% or more inhibitor, preferably at a test compound concentration of 1><10'9 mol/L It is a compound with activity. Also, the compound preferably has an inhibitory coefficient (Ki value) of 30 A compound with an inhibitory activity of nmol/L or less, more preferably 10 nmol/L or a compound with a lower inhibitory activity, more preferably 3 nmol/L or a compound with a lower inhibitory activity, more preferably 1 nmol/L or less It is a compound with a low inhibitory activity.

Also, Compound (I) or a pharmaceutically acceptable salt thereof Selective for adenosine AZA receptors among various subtypes of adenosine receptors It is a compound with affinity. For example, adenosine AZA relative to adenosine A1 receptors A compound with a higher affinity for its receptors is preferred. Specifically, for example, the compound has affinity for adenosine AZA receptors, preferably for adenosine A1 receptors 5 times or more, more preferably 10 times or more, more preferably 50 times the affinity times or more, more preferably 100 times or more, most preferably It is a compound with a multiple of 500 or more.

For adenosine receptors, attenuation can be carried out by a conventional method, for example the Test mentioned below. According to the procedure of Example 1 or in a document [for example, Naunyn Sehmiedebergs Arch can be determined.

More specifically, Compound (1) preferably Rylin optionally halogen, optionally CH, alkoxy or CH substituted with morpholino, alkyl, CH, alkanoyl, vinyl and CH, alkoxy phenyl substituted with 1 to 3 substituents selected from; optionally halogen, optional C1-6 alkyl, C1-6 alkanoyl, vinyl and pyridyl substituted with 1 to 3 substituents selected from CM alkoxy; optionally halogen, CH, alkyl, C1- optionally substituted with C1-alkoxy or morpholino pyrimidinyl substituted with 6 alkanoyl, vinyl and CH) alkoxy; optionally halogen, Ci- 5,6-dihydro-2H- substituted with 1 to 3 substituents selected from 6 alkyl and CH, alkoxy pyridylmethyl; 2,3,4,5-tetrahydropyranyloxy; pyrrolyl; indolyl; oxazolopyridyl; quinolyl; 1H-3,4- dihydropyranopyridinyl; 1H-3,4-dihydrothi0pyranopyridinyl; cyclopentapyridyl; or pyridylmethyl a compound, more preferably Rhin, optionally a fluorine atom, a chlorine atom, methyl phenyl substituted with 1 to 3 substituents selected from and methoxy; on demand a a fluorine atom, a chlorine atom, substituted with 1 to 3 substituents selected from methyl and methoxy extracted pyridyl; optionally between a fluorine atom, a chlorine atom, methyl and methoxy pyrimidinyl substituted with 1 to 3 selected substituents; optionally a fluorine atom 5,6-substituted with 1 to 3 substituents selected from chlorine atom, methyl and methoxy dihydro-2H-pyridylmethyl; or 2,3,4,5-tetrahydropyranyloxy; even more preferably R1 is a chlorine atom, substituted with 1 to 3 substituents selected from methyl and methoxy pyridyl; a chlorine atom substituted with 1 to 3 substituents selected from methyl and methoxy pyrimidinyl; 5,6-dihydro-2H-pyridylmethyl; or 2,3,455-tetrahydropyranyloxy.

More specifically, Compound (I) is preferably compounds of formula (IA) - (IAA) below and (The compound used in this invention is the compound of formula (IC).) i lA ;I'J ji I 4 I 'E' 4 _ \ h *4 .1 M M of. JJ; :TWO ..IL . 3 '3 i i 'i-.i ` . jnii ;ini i›U' iIP i 5:› l 1;. i i iS ( i l' Among the pharmaceutically acceptable salts of compound (I), for example, pharmaceutical acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Compound (I)7in pharmaceutically acceptable acid Addition salts include inorganic salts such as hydrochloride, hydrobromate, nitrate, sulfate and phosphate. acid salts; organic acid such as acetate, oxalate, maleate, fumarate, citrate, benzoate and methane sulfonate salts] and the like. Examples of pharmaceutically acceptable metal salts alkali metal salts such as a sodium salt and a potassium salt; a magnesium salt and alkaline earth metal salts such as a calcium salt; an aluminum salt; a zinc salt and similar place. Examples of pharmaceutically acceptable ammonium salts include ammonium, tetramethylammonium salts and the like. pharmaceutically acceptable Examples of organic amine addition salts include morpholine, piperidine addition salts or the like. takes place. Examples of pharmaceutically acceptable amino acid addition salts include lysine, glycine, phenylalanine, aspartic acid, glutamic acid addition salts, or the like. can be produced accordingly. where R1 and R2 are as defined above and X is a chlorine atom, a bromine atom or is similar.

As shown specifically in the above-mentioned formula, Compound (1), for example WO methanol, dichloromethane, chloroform, toluene, ethyl at a temperature between boiling point acetate, acetonitrile, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), pyridine, water or a mixture thereof and the like, preferably 1 to 5 equivalent carbodiimide In the presence of a condensing agent (EDC) hydrochloride or the like, preferably if necessary 1 to 5 equivalents of 1-hydroxybenzotriazole (HOBt) monohydrate 4-dimethylaminopyridine (DMAP) and preferably by reacting with 0.5 to 5 equivalent compounds (Ib) in the presence of the like can be produced.

At a temperature between °C and 150 °C, without solvent or dichloromethane, chloroform, 1,2- a solvent such as dichloroethane, toluene, ethyl acetate, acetonitrile, THF, DMF, DMA, pyridine, and the like preferably 1 to 10 equivalents of potassium carbonate, triethylamine, 4- if necessary preferably with 1 to 10 equivalent compounds (Ic) in the presence of dimethylaminopyridine (DMAP) and the like It can also be produced by reacting

Stereoisomers or tautomers, such as compound (I) geometric isomers or optical isomers may exist as

All possible isomers, including these and their mixtures, a substance, a pharmaceutical composition, for the treatment and/or prophylaxis of A substance, a kit, an action for the treatment and/or prophylaxis of Parkinson's disease a method, a combination, an action for the treatment and/or prophylaxis of use for the manufacture of a substance for the treatment and/or prophylaxis of For the manufacture of an agent for the treatment and/or prophylaxis of Parkinson's disease available for use.

When Compound (1) is obtained in the form of a salt, to obtain a salt of Compound (I), can be purified as Also, when the compound is obtained in a free form, the compound is a suitable can be dissolved or suspended in solvent and then formed to form a salt An acid or a base may be added for The resulting salt can then be isolated and can be purified.

Compound (IC) or a pharmaceutically acceptable salt thereof with water or various solvents. may exist in the form of a plugin. This appendix is also a thiazole derivative of the present invention or its a pharmaceutically acceptable salt thereof.

A pharmaceutical composition, an agent for the treatment and/or prophylaxis of Parkinson's disease, a kit, a method for the treatment and/or prophylaxis of Parkinson's disease, a combination, For the manufacture of an agent for the treatment and/or prophylaxis of Parkinson's disease L-DOPA used for use as an active ingredient, L-DOPA or a salt thereof, may contain the hydride, prodrug or the like and, for example, a product containing them as active ingredients. compound and the like can be used. This L-DOPA can be obtained as a commercial product, for example. or by a known method. Specific examples of products available on the market include Menesit (registered trademark), EC Doparl (registered trademark), Doparl (registered trademark), Madopar (registered trademark) and the like.

A pharmaceutical composition, an agent for the treatment and/or prophylaxis of Parkinson's disease, a The kit is a method for the treatment and/or prophylaxis of Parkinson's disease, a combination and For the manufacture of an agent for the treatment and/or prophylaxis of Parkinson's disease the dopamine agonist used for use as an active ingredient a dopamine agonist or may include a salt, hydrate, prodrug or the like thereof, and may be used, for example, as active ingredients. a composition containing them and the like can be used. Specific examples include pramipexole, talipexole, ropinirole, cabergoline, pergolite and the like or a hydrochloride thereof, mesylate, precursor medicament and the like, and a composition containing them as active ingredients and the like. can be used. This dopamine agonist can be obtained, for example, as a commercial product or can be produced by a known method. Specific examples of commercially available products include Domin (registered trademark), Perrnax (registered trademark), Cabaser (registered trademark) and so on takes place.

Suitable for a substance of this invention for the treatment and/or prophylaxis of a movement disorder pharmaceutical composition and a treatment for and/or prophylaxis of a movement disorder use for the manufacture of the substance, alone or in any other form, as the active ingredient Compound (IC) as a mixture with the therapeutic active ingredient, or its pharmaceutical may contain an acceptable salt. In addition, these pharmaceutical compositions contain one or more of the active ingredients. with more pharmaceutically acceptable carriers (e.g. diluents, solvents, excipients or the like) by mixing and then mixing well in the field of pharmaceutical technical prepared by any known method.

Regarding the route of administration, it is preferable to choose the most effective route of administration for the treatment.

Examples of routes of administration include oral administration and parenteral administration, for example intravenous or transdermal administration and the like.

Examples of dosage forms include tablets, injections, external preparations and the like. Dosage forms suitable for oral administration, eg tablets, excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate or binders such as hydroxypropylcellulose or the like.

Dosage forms suitable for parenteral administration, for example, injections, a saline solution, a glucose solution or a mixture of saline and glucose solution or diluents such as or using solvents. Relating to a dosage form suitable for the external preparation There are no special restrictions and eg ointment, cream, liquid ointment, lotion, yaki, plaster, tape and so on. For example, ointment, cream and similar, for example, the active ingredient is white vaseline and can be produced by dissolving or mixing-dispersion in a base such as this.

Dosage and frequency of administration of compound (1) or a pharmaceutically acceptable salt thereof efficacy, dose and/or administration form, patient's age and body weight, to be treated varies depending on the characteristics or severity of symptoms and the like. by word of mouth For administration, 0.001 - 1000 mg to an adult, preferably in one to several servings per day 0.05 - 100 mg is administered. For intravenous administration and the like for parenteral administration 100 mg is administered. For transdennal administration, 0.001%-10% Compound (I) or its an external preparation containing a pharmaceutically acceptable salt of applied several times. However, these doses and frequency of administration may differ from the above-mentioned various varies depending on the circumstances.

The substance of this invention and a substance for the treatment and/or prophylaxis of a movement disorder. Thiazole derivative for use in the treatment and/or prophylaxis of movement disorder or a pharmaceutically acceptable salt thereof, extrapyramidal syndrome, bradykinesia, gait disturbance, dystonia, dyskinesia, tardive dyskinesia, or a movement disorder like the one; and end-of-dose phenomenon, on-off fluctuation, dyskinesia, or L-DOPA and/or the like a superior therapeutic and/or prophylactic over a side effect of dopamine agonist therapy or has a reducing and/or suppressive effect. Specifically, Parkinson's in an advanced stage the above-mentioned discomfort that occurs in the disease (for example, extrapyramidal syndrome, bradykinesia, gait disturbance, dystonia, dyskinesia, tardive dyskinesia, or any such movement disorder; and end-of-dose phenomenon, on-off fluctuation, dyskinesia or L-DOPA like and/or a side effect of dopamine agonist therapy) on a superior therapeutic and/or It has a prophylactic or reducing and/or suppressive effect.

As mentioned above, Compound (1) or a pharmaceutically acceptable salt thereof may be used in combination with one or more other pharmaceutical ingredients.

Examples of other pharmaceutical ingredients used in combination include Parkinson's disease. useful as a therapeutic and/or prophylactic drug and the like for disease and the like known drugs are included (Iyaku (Medicine and Drug) Journal, vol. 44, p. 91 (2008)). Specific eg COMT inhibitors (eg entacapone, tolcapone and the like), MAO inhibitors (eg, selegiline, razagiline and the like) and the like may be included.

Compound (1) or a pharmaceutically acceptable salt thereof When used in combination with the component(s), Compound (1) or its pharmaceutical an acceptable salt and other pharmaceutical ingredient(s) simultaneously or separately can be applied intermittently. Doses depend on the patient being treated, the route of administration, the disease and the varies depending on the pharmaceutical ingredient combinations and the like and the clinically used should be determined by dose.

(a) Compound (IC) or its pharmaceutical composition used for the pharmaceutical composition and kit of this invention and (b) L-DOPA and/or a dopamine agonist. (combination agent) or as a combination of more than one compound or applicable, but these compositions are for example pharmaceutically acceptable to contain these active ingredients. formulated with an acceptable carrier. In particular, a combination of two or more combination is preferred. used as a combination of more than one compound or When administered, the compositions may be used intermittently, either simultaneously or separately. or applicable. Preferably these compositions are eg tablets, injections, external preparations or used in a similar form. (a) The compound (IC) or a pharmaceutically acceptable salt thereof; and (b) L-DOPA and/or the dose ratio (w/w) of a dopamine agonist, (a) Compound (I) or a pharmaceutically acceptable salt thereof; and (b) L-DOPA and/or a dopamine agonist to the combination, (a) Compound (1) or a pharmaceutically acceptable combination thereof salt and (b) L-DOPA and/or a dopamine agonist according to the efficacy of each and the like. an acceptable salt is/(b) L-DOPA and/or a dopamine agonist).

These compositions are composed of the active ingredient with one or more pharmaceutically acceptable carriers. (eg diluents, solvents, excipients or the like) by stirring and then mixing It is prepared by any method well known in the pharmaceutical art.

Dosage forms suitable for oral administration, eg tablets, excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, hydroxypropylcellulose It can be prepared using binders such as

Dosage forms suitable for parenteral administration include, for example, injections, a saline solution, a glucose solution or a mixture of saline and glucose solution or diluents such as or using solvents. Relating to a dosage form suitable for the external preparation There are no special restrictions and eg ointment, cream, liquid ointment, lotion, yaki, plaster, tape and so on. For example, ointments, creams and similar, for example, the active ingredient is white petrolatum and can be produced by dissolving or mixing-dispersion in a base such as this.

When administered as a combination of more than one compound, for example (a) Compound (IC) or a first component comprising a pharmaceutically acceptable salt thereof; and (b) L-DOPA and/or a second component comprising a dopamine agonist may be prepared separately in a kit and using the kit, to the same patient in the same way or by different means, simultaneously or separately As a kit, for example, the contents of the containers and the contents of the containers depending on the external temperature or light. that the components do not decompose and that the chemical components during storage not cause elution from containers and the contents of the above first and second components a system that allows it to be administered in separate ways (eg tubes and the like) or in the same way. without any special restrictions as to its material, shape and the like, provided that it has the form A kit containing two or more containers (eg vials, bags, etc.) is used.

Specific examples include tablet kits, injection kits and the like. (a) The compound (IC) or a pharmaceutically acceptable salt thereof; and (b) L-DOPA and/or a dopamine agonist for the above-mentioned purposes as one of more than one composition When used or administered as a combination, dose and frequency of administration, each factor depending on the efficacy of the ingredient, the dosage form, the age and body weight of the patient, symptoms and changes depending on the like. (a) The compound (IC) or its pharmaceutically acceptable a salt and (b) L-DOPA and/or a dopamine agonist each usually per day It may be preferable to apply in the following dose. For oral administration, for example as a tablet, (a) Compound (IC) or its pharmaceutical an acceptable salt and (b) L-DOPA and/or a dopamine agonist usually taken simultaneously or separately as single or several divided portions per day. applied at the level. For parenteral administration, for example by injection and the like, (a) Compound (IC) or its a pharmaceutically acceptable salt; and (b) L-DOPA and/or a dopamine agonist. to adult, usually as single or several divided portions per day (a) The compound (IC) or a pharmaceutically acceptable salt thereof; and (b) L-DOPA and/or a dopamine agonist as a single compound for the above-mentioned purposes when used or administered, the dose and frequency of administration, the efficacy of each active ingredient, the dosage form varies depending on the patient's age and body weight, symptoms and the like.

If a combination of more than one of the above-mentioned compounds is in use or preparation of a composition containing each dose in practice and its use or implementation is preferred.

However, this dose and frequency of administration varies depending on the conditions mentioned above.

A pharmaceutical composition of this invention, and a combination On-off fluctuation and end-of-dose phenomenon due to L-DOPA treatment or the like It can be used in patients with Parkinson's disease where symptoms occur and can effectively treat these diseases. can be treated in the same way.

Movement disorders of the compound (1) or a pharmaceutically acceptable salt thereof (a) Compound (1) or a pharmaceutically acceptable salt thereof; and (b) The effect of combined administration of L-DOPA and/or a dopamine agonist and the like is as follows: It is specifically described in the Test Examples.

Test Example 1. Adenosine Receptor Binding Effect (1) Adenosine AZA Receptor Binding Test The test was carried out, for example, according to the procedure of Varani et al. (British Journal of Pharmacology, 1996, 1 17, according to page 1693).

Specifically, for example, human recombinant receptors are expressed in HEK-293 cells.

Cell membranes of cells expressing the receptor aggregate and form a cell membrane. suspension is prepared. Buffer Tris(hydroxymethyl)-aminomethane hydrochloride (Tris HCl) After dilution, tritium-labeled CGS-21680 (3H-2-[p-(2-) carboxyethyl)phenethylamino)-5'-(N-ethylcarboxamido)adenosine: 50 mmol/L) and a test compound solution (dimethyl sulfoxide solution of the test compound) for binding to the receptors. added to the membrane suspension. After the reaction, the mixture is filled with glass fiber filter paper. The radioactivity of the glass fiber filter paper is subjected to fast suction filtration using is measured. Thus, the binding of the test compound to the human adenosine AZA receptor (3H-CG821680) binding) inhibition rate can be determined.

Test according to the procedure of Bruns et al. (Molecular Pharmacology, Vol. 29, p. 331, 1986) can also be applied.

Specifically, for example, the rat striatum is 50 mL using a Polytron homogenizer. suspended in Tris HCl buffer (50 mmol/L, pH 7.7) at ice cold and the suspension is centrifuged. The resulting precipitate was added to Tris HCl buffer (50 mmol/L). It is resuspended and passed through the centrifuge in the same way. 5 mg (wet weight)/mL tissue concentration, resulting in the final precipitate to prepare the suspension Tris HCl buffer (50 mmol/L) [magnesium chloride (10 mmol/L) and adenosine deaminase (contains 0.02 units/mg tissue)] is suspended. CGS-21680 marked with tritium (final concentration 6.0 mmol/L) and test compound solution (Tris HC] diluted with buffer dimethylsulfoxide solution of the test compound) is added. Mixture 120 minutes at 25°C After waiting, it is subjected to fast suction filtration using glass fiber filter paper and then immediately washed with ice-cold Tris HCl buffer (50 mmol/L). glass fiber filter paper it is then placed in a vial and MicroScinti (PKI) is added. Then the radioactivity The rat adenosine A2A receptor of the test compound as measured by TopCount (Perkinelmer) Inhibitor ratio can be determined for binding (3H-CGS21680 binding).

The inhibitory ratio can be calculated with the following equation.

Total amount of binding - amount of non-specific binding n; In the equation, the total amount of binding is bound to 3JH-CG3216809 in the absence of the test compound. indicates its radioactivity. Amount of non-specific binding, 50 µmol/L 5'-N- in the presence of ethylcarboxamidadenosine (NECA) or Indicates the bound radioactivity of 3H-CGSZI 680. Test the amount of binding in the presence of the drug 3H-CGSZ indicates the bound radioactivity of 680° in the presence of the compound.

In the above test, the test compound or a pharmaceutically acceptable salt thereof test compound at different concentrations and in which the test compound inhibits binding by 50% At concentration (IC50), the inhibitory ratio for the adenosine AZA receptor was equal to that of the test compound. can be calculated by adjusting the concentration appropriately.

Inhibition coefficient (Ki value) of the test compound for adenosine AZA receptor binding can be calculated according to the following equation.

Ki = :jazz/(1 + L/Kd) In the equation, L denotes the concentration of 3H-CG321680 used in the test, and Kd in the test. 3 is the separation coefficient of the H-CG821680a used. 3H-CGSZlpyrazolo[4,3-e]- 1,2,4-triazolo[1,5-c]pyrimidine) and the like can be used. (2) Adenosine A1 Receptor Binding Test The inhibition coefficient (Ki value) of the test compound for the adenosine Ai receptor is the same as in (1) In the figure, it can be calculated using the following materials.

Specifically, CHO cell membranes are used that express, for example, the human A1 receptor. and as the labeled compound, for example, tritium-labelled DPCPX (1,3-dipropyl-8- cyclopentylxanthine) is used. Non-specific binding eg - By measuring the 3H-DCPPX-bound radioactivity in the presence of NO-Z-phenylisopropyl adenosine), can be determined. The affinity of the test compound for human adenosine A1 receptors is thus confirmed. can be done.

Alternatively, for example, rat A1 receptor-expressing cell membrane (PerkinElmer) used and as the marked compound, for example, tritium-labeled CHA (N6- cyclohexyladenosine) is used. For the measure of the amount of non-specific binding, 3H-CHA bound radioactivity is measured in the presence of, for example, 10 µmol/L DPCPX and the test compound is its affinity for the adenosine A1 receptor can be confirmed.

With the above test (1) and (2), the thiazole derivative used in this invention or its pharmaceutical selective affinities for the adenosine A1 receptor can be confirmed. (3) Adenosine receptors of the compound (1) or a pharmaceutically acceptable salt thereof affinity for.

The adenosine A1 receptor of the compound (1) or a pharmaceutically acceptable salt thereof, and Some examples of their affinity for the adenosine AZA receptor are presented below. The following test of the results of MDS Pharma Services Inc. measured according to the above methods by note (Compound (IA), (IAB) and (ID) are Reference Examples).

Table 1. Affinities for adenosine receptors compound Human adenosine A2A receptor Human adenosine A1 receptor no. connecting (3H-CGS) for inhibitory rate* for inhibitory rate* (1A) 92% 14% * Inhibitory rate at 100 nmol/L compound level Test Example 2. Adenosine Receptor Binding Activity (2) In the same way as in the Test Sample List mentioned above, the compound (IE) - (IAA)° (Reference samples) confirmed affinity for the adenosine receptor (test results from Ricerca Biosciences, were the results measured by the LLC according to the above procedures).

Table 2. Affinities for adenosine receptors Compound Human adenosine Human adenosine compound Human adenosine Human adenosine no. AZA receptor A1 receptor No. A2A receptor A1 receptor connecting (3H- for connecting) inhibitory rate* connecting (3H- for connecting) inhibitory rate * connecting (3 H- for connecting) inhibitory rate * connecting (3 H- for connecting) inhibitory rate)* * Inhibitory rate at 100 nmol/L compound level Confirmation from the above tests that Compound (I) has selective affinity for the adenosine AZA receptor. is being done.

Test Example 3. The L-DOPA and thiazole derivative of this invention or its pharmaceutically acceptable 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine of the combination consisting of a salt (MPTP) treatment on the silk monkey in which the symptoms of Parkinson's disease occur. therapeutic effect Parkinson's disease, progressive dopaminergic neuron degradation in the black matter-striatum and It is a disease caused by loss. In primates, MPTP is a dopamine neurotoxin. treatment causes selective dopaminergic neuron degradation and loss in the black matter-striatum. primates are known as Parkinson's disease models [Proceedings of the National monkeys (Haplorhini) and, like other black-nosed monkeys, MPTP Known to show symptoms of Parkinson's disease [Neuroscience Letter, vol. 57, p. 37 ( Silk once a day for 5 days monkey (CLEA Japan, Inc.) was administered subcutaneously to the dorsal and from the first application. MPTP 1-2 mg/kg subcutaneously once or twice after approximately 3 weeks chronic Parkinson's symptoms (low locomotor activity, bradykinesia, gait disorder, abnormal postures, less coordinated movements, decreased vocalization and silk monkey (MPTP-treated silkworm) was prepared and silk The monkey was used for testing. Parkinson's symptoms indicator described in a previous report [Annales of Neurology, vol. 43, p. 507 (1998)]. Observation items and scores are shown in Table 2. All compounds 0.5% MC400, 10% aqueous used as a suspension in sucrose solution. Animal media preconditioning were placed in an observation cage the day before test compound administration. (with locomotor activity meter). Symptoms of Parkinson's disease are one-sided was continuously monitored with a mirror and the disability score was determined every 10 minutes for 6 hours.

Table 3. Disability Assessment Scale Used in Silk Monkeys Substances 0 1 2 3 4 Wakefulness Normal Decreased Sleepiness - - Control Movement Yes Decreased No - - Attention Blink Normal Abnormal - - - abnormality in body, arm, leg, tail: each Posture Normal one 1 point Abnormal Balance/Coordination Normal Impaired Unstable Falls - Response to stimuli Normal Decreased Slow None - Vocalization Normal Decreased None - - Locomotor activity is calculated automatically using a computer with a photocell measuring instrument. inhibitor (contains benserazide hydrochloride), MPTP treated silk Parkinson's symptoms in the monkey decreased with increasing dosage. 1 mg/kg of compound (IC) and L-DOPA administered orally simultaneously. Compound (ICY (1 mg/kg) with various doses of L-DOPA administration of L-DOPA prolonged the anti-Parkinsonian activity and also L-DOPA alone It increased the maximum effects of DOPA. l mg/kg compound (IC) and 10 mg/kg L-DOPA physical disability score when administered orally in combination The process of impact on it is shown in Figure 1. l mg/kg compound (IC) and 10 mg/kg L-DOPA When administered orally simultaneously in combination, the duration of action (“on” duration) increased compared to 10 mg/kg L-DOPA treatment alone. In addition, 1 mg/kg of compound (IC) and each contains) when administered orally simultaneously in combination and L- Maximum improvement in disability score when treated with DOPA* is also shown in Figure 2. 1 mg/kg of compound (IC) and each dose of L-DOPA in combination Maximum effects are achieved with each dose of L-DOPA when administered concomitantly orally. the maximum intensity of increase increased.

From the above-mentioned test, Compound (1) in L-DOPA's effect on Parkinson's disease enhancing its therapeutic effect and the therapeutic effect of L-DOPA on Parkinson's disease It is understood that there are effects of prolonging the duration.

Test Example 4. The L-DOPA and thiazole derivative of this invention or its pharmaceutically acceptable combination of an acceptable salt, where motor complication occurs The therapeutic effect of MPTP in each treated marmoset. mg/kg L-DOPA (contains 2.5 mg/kg benserazide hydrochloride) Chronic with MPTP therapy Silk monkey with Parkinson's symptoms (MPT-treated silk monkey) gavage twice a day at approximately 6-hour intervals by the method described in Test Example 3. Done. Motor in the marmoset treated with MPTP as well as Parkinson's symptoms complication (dyskinesia symptom, end-of-dose phenomenon, on-off fluctuation and so on) L-DOPA was applied repeatedly for more than 3 weeks and the silk monkey test was used for. Parkinson's symptoms as described in a previous report as in Test Example 2. assessed using a rating scale [Annales of Neurology, vol. 43, page 507 (1998')]. Locomotor activity is automated using a photocell measuring instrument and a computer. was measured. All compounds 0.5% MC400 in 10% aqueous sucrose solution was used as a suspension. Test compound for preconditioning to animal environment was placed in an observation cage (locomotor activity measurement with the tool). Parkinson's disease symptoms monitored continuously with a one-way mirror and disability score was determined every 10 minutes for 6 hours. 2.5 mg/kg or 10 mg/kg L- When DOPA (containing 2.5 or 0.625 mg/kg benserazide hydrochloride) is administered, treatment with MPTPS Parkinson's symptoms in the treated silkworm decreased with increasing dosage. l mg/kg of compound (IC) and 2.5 mg/kg L-DOPA were administered simultaneously in combination with gavage. Conclusion As a result, L-DOPA's anti-Parkinson activities are prolonged (“on” time) L-DOPA 2.5 mg/kg per treatment for approximately 50 minutes, combined with 1 mg/kg compound (IC) approx. 150 minutes with practice) and increase in activity (minimum disability score alone is L- 5.33±0.80, with DOPA 2.5 mg/kg treatment combined with 1 mg/kg compound (lC) 3.83±0. l 7) observed.

From the results of Test Example 4 mentioned above, the side effect of Compound (I) of L-DOPA The end-of-dose phenomenon is thought to have an effect on suppression.

Test Example 5. The L-DOPA and thiazole derivative of this invention or its pharmaceutically acceptable with MPTP where motor complication occurs effect on dyskinesia in the treated marmoset mg/kg L-DOPA (containing 2.5 mg/kg benserazide hydrochloride) By the method described in test sample 33 Silk monkey (with MPTP) in whom chronic Parkinson's symptoms occur with MPTP therapy silk monkey treated) was applied twice a day with an interval of approximately 6 hours. with MPTP symptoms of Parkinson's as well as motor complication in the treated marmoset (symptom of dyskinesia, end-of-dose phenomenon, on-off fluctuation and so on) L-DOPA was administered repeatedly for more than 3 weeks and the silk monkey was used for testing.

As in Dyskinesia Severity Test Example 2, a previous report [Annales of Neurology, vol. 43, p. 507 (1998)] were evaluated using the rating scale described. Evaluation items and Scores are shown in Table 3. All compounds 0.5% MC400, 10% aqueous used as a suspension of sucrose solution. For preconditioning the animal to the environment was placed in an observation cage the day before test compound administration (locomotor activity with measuring instrument). Dyskinesia symptoms were observed in a one-way mirror and lasted 6 hours. recorded every 20 minutes.

Table 4. Dyskinesia Rating Scale Used in Silk Monkeys assessment item score No dyskinesia 0 Temporary and infrequent dyskinetic postures mild l Abnormal 2 that is more pronounced but does not significantly interfere with normal behavior movements The continuous emergence of abnormal behavior to affect normal behavior is evident. Mostly abnormal behavior and no normal animal movements severe 4 Locomotor activity is automatically determined using a computer with a photocell measuring instrument. and 2.5 mg/kg of benserazide hydrochloride) with increasing dose of L-DOPA Dyskinesia occurred in the marmoset treated with MPTPly. 1 mg/kg of compound (IC) and L-DOPA combination was administered orally simultaneously. l mg/kg of the compound (lC) for each L-DOPA contains) combined administration is a serious problem for administration of any single dose of L-DOPA. It did not aggravate the dyskinesia that caused it. Compound alone (IC) at a dose of 0.1 to 10 mg/kg When applied, dyskinesia did not occur.

Dyskinesia, a side effect of Compound (I),in, L-DOPA, from the above-mentioned test. It was concluded that it did not increase. From the results of Test Samples 3 - 5, L-DOPA and Compound (I) and such a thiazole derivative, which is a side effect of L-DOPA. does not increase dyskinesia, but the therapeutic effect of L-DOPA on Parkinson's disease (increasing and prolonging the effect of L-DOPA).

From Test Examples 3-5 mentioned above, Compound (1) or its pharmaceutically acceptable L-DOPA and/or for Parkinson's disease or the like side effects of dopamine agonist therapy (eg, end-of-dose phenomenon, on-off fluctuation, dyskinesia or similar). Specifically, Compound (1) L-DOPA and/or dopamine agonist, or a pharmaceutically acceptable salt thereof It is concluded that it is effective in reducing the end-of-dose phenomenon in the treatment of

In addition, Compound (I) or a pharmaceutically acceptable salt thereof and L-DOPAlnin combined use may reduce Parkinson's symptoms (bradykinesia, gait, akinesia or and similar movement disorders). Moreover Compound (1) or a pharmaceutically acceptable salt thereof in combination with L-DOPA When used in combination, ameliorative effects on Parkinson's symptoms and locomotor activity one effect is stronger than the use of L-DOPA alone. Hence Compound (1) or a combined use of a pharmaceutically acceptable salt thereof and L-DOPA, L-dose needed to achieve the same level of improvement as a treatment with L-DOPA alone. It can reduce the dose of DOPA and prevent side effects in the circulatory and gastrointestinal systems. as well as suppress or suppress the onset of L-DOPA-induced dyskinesia and motor complications. can delay.

In the following, this invention is more specifically described by Examples.

Tablets with the following formulations are prepared in the conventional manner. Compound (1A) (40 g), Lactose (286.8 g) and potato starch (60 g) are mixed and then 10% aqueous hydroxypropylcellulose solution (120 g) is added. The resulting mixture is traditionally It is kneaded, granulated and dried to form granules for tabletting. To this 1.2 g After adding magnesium stearate, the mixture is formed into a tablet with a punch diameter of 8 mm. stapling with a machine (Model RT-15; Kikusui) (containing 20 mg of active ingredient per tablet) tablets are obtained.

Formulation Compound (1A) 20 mg lactose 143.4 mg potato starch 30mg hydroxypropylcellulose 6mg magnesium stearate 0.6mg 200mg Tablets with the following formulation are prepared in the same way as in Example 1.

Formulation Compound (IB) 20 mg lactose 143.4 mg potato starch 30mg hydroxypropylcellulose 6mg magnesium stearate 0.6mg 200mg [Example 3] Tablets with the following formulation are prepared in the same way as in Example 1.

Formulation Compound (IC) 20mg lactose 143.4 mg potato starch 30mg hydroxypropylcellulose 6mg magnesium stearate 0.6mg 200mg Tablets of the following formulation are prepared in a conventional manner. Compound (IA) (40 g), hydroxypropylcellulose solution (120 g) is added. The resulting mixture is traditionally It is kneaded, granulated and dried to form granules for tabletting. 12 g to this After magnesium stearate has been added and mixed, the mixture is made into a tablet with a diameter of 8 mm. machine (Model RT-15; Kikusui) (compound (IA) per tablet (20 mg) and L- DOPA (20 mg) tablets are obtained.

Formulation Compound (1A) 20 mg L-DOPA 20mg lactose 123.4 mg potato starch 30mg hydroxypropylcellulose 6mg magnesium stearate 0.6mg 200mg Tablets with the following formulation are prepared in the same way as in Example 4.

Formulation Compound (IB) 20 mg L-DOPA 20mg lactose 123.4 mg potato starch 30mg hydroxypropylcellulose 6mg magnesium stearate 0.6mg 200mg Tablets with the following formulation are prepared in the same way as Example 4.

Formulation Compound (IC) 20 mg L-DOPA 20mg lactose `123.4 mg potato starch 30mg hydroxypropylcellulose 6mg magnesium stearate 0.6mg 200mg Injections with the following formulation are prepared in a conventional way. Compound (IA) (1 g) is added to distilled water for injection and then mixed. pH of the mixture After adjusting to 7° by adding hydrochloric acid and sodium hydroxide aqueous solution, The total volume is adjusted to 1,000 mL with distilled water for injection. The resulting mix 2 Filling aseptically into glass vials (2 mg per vial) in mLalic portions. injections containing the active ingredient are obtained.

Formulation Compound (IA) 2 mg hydrochloric acid Appropriate amount aqueous sodium hydroxide solution Appropriate amount appropriate amount of damitilinis water for injection 2.00mL Injections with the following formulation are prepared in the same way as in Example 1.

Formulation Compound (IE) 2 mg hydrochloric acid Appropriate amount aqueous sodium hydroxide solution Appropriate amount Distilled water for injection Appropriate amount 2.00mL Injections with the following formulation are prepared in the same way as in Example 71.

Formulation L-DOPA 2mg hydrochloric acid Appropriate amount aqueous sodium hydroxide solution Appropriate amount Distilled water for injection Appropriate amount 200 mL Injections with the following formulation are prepared in a conventional way. Compound IA (1 g) and L-DOPA (1 g) are mixed after adding distilled water for injection. my wife's After adjusting the pH to 7 by adding hydrochloric acid and a sodium hydroxide aqueous solution The total volume is then adjusted to 1,000 mL with distilled water for injection. Obtained The mixture is filled aseptically in 2 mL portions into glass vials (vials). Compound (IA) (2 mg) and L-DOPA (2 mg) injections per head are obtained.

Formulation Compound (IA) 2 mg L-DOPA 2mg hydrochloric acid Appropriate amount aqueous sodium hydroxide solution Appropriate amount Distilled water for injection Appropriate amount 2.00mL Injections with the following formulation are prepared in the same way as in Example 10.

Formulation Compound (IC) 2 mg L-DOPA 2mg hydrochloric acid Appropriate amount aqueous sodium hydroxide solution Appropriate amount Distilled water for injection Appropriate amount 2.00mL N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl)-6-vinylpyridine-3-carboxamide (Compound IE) step 1. Methyl 6-k10ronik0tinate (dissolved in vinyltributyl tin ( and The mixture was allowed to cool to room temperature and an aqueous solution of potassium fluoride was added to it. was done. The mixture was filtered through Celite and the residue was washed with ethyl acetate. The resulting filtrate is a Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. was done. The organic layer was washed with saturated brine, over anhydrous magnesium sulfate. dried and concentrated under reduced pressure. The resulting residue silica gel column solution (8 mL). To this was added lithium hydroxide monohydrate (276 mg, 6.57 mmol). and the mixture was stirred for 1 hour at room temperature. After the mixture is cooled to 0°C, 3 mol/L hydrochloric acid (3 mL) was added and the precipitated solid was collected by filtration. Vinylnicotinic acid (309 mg, 70%) was obtained as a white solid. il=ketone ( dissolved in EDC hydrochloride (412 mg, and the mixture was stirred at 50°C for 5 hours. The mixture was left to warm to room temperature, water and a saturated aqueous sodium hydrogen carbonate solution were added and the mixture was diluted with ethyl acetate. extracted. The organic layer was washed with saturated brine, anhydrous magnesium sulfate. dried over and concentrated under reduced pressure. The resulting residue silica gel purified by column chromatography (hexanzetyl acetate=50i50) and reconstituted from ethanol-water crystallized to give Compound IE (1.22 g, 85%) as white crystals. 2.4 Hz, 1H), 9.84 (brs, 1H). ESIMS in/z: [M+H]+ 410.

N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-(pyridin-3-yl)acetamide (Compound 2.14mmol) was added and the mixture was stirred overnight at 80°C. Mix to room temperature allowed to cool and water and a saturated aqueous solution of sodium hydrogen carbonate were added to it. was done. The precipitated solid was collected by filtration and dried under reduced pressure. The resulting solid It was eluted by silica gel column chromatography (hexanzetyl acetate=50r50) and ethanol was removed from the water. recrystallized to give Compound IF (112 mg, 75%) as white crystals.

N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-1H-pyrrole-Z-carboxamide (Compound IG) obtained as pale brown crystals from carboxylic acid (240 mg, 2.18 mmol). (brs, 1H) . APCIMS m/z: [M+H]+ 372.

N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-1H-indole-4-carboxamide (Compound IH) obtained from carboxylic acid (331 mg, 2.05 mmol) as milky white crystals. (brs, 1H), 9.70 (brs, 1H). APCIMS m/z: [M+H]+ 422.

N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-(morpholin-4-ylmethyl)pyridin-4- carboxamide (Compound II) i1=ket0n ( dissolved in EDC hydrochloride (5.50 g, and by the method described in WOO3/043636 The resulting 2-(chloromethyl)isonicotinic acid (493 g, 287 mmol) was added and the mixture was stirred overnight. was stirred at 80°C throughout. The mixture was allowed to cool to room temperature and was added to it with water and a saturated aqueous sodium hydrogen carbonate solution was added. The precipitated solid was collected by filtration. and dried under reduced pressure. The obtained solid silica gel was obtained by column chromatography. carbonyl)thiazol-2-yl]pyridine-4-carboxamide (700 mg, 23%) as a pale brown solid step 2. 2-(chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-) obtained in step 1 carbonyl)thiazol-2-yl]pyridine-4-carboxamide (70.0 mg, 0.162 mmol) acetonitrile (in After dissolving, morpholine was added to it and the mixture was refluxed for 1 hour. stirred under heating. The mixture was allowed to cool to room temperature, followed by water and a saturated aqueous sodium hydrogen carbonate solution was added. The mixture is extracted with ethyl acetate. and the organic layer was washed with saturated brine, over anhydrous magnesium sulfate. dried and concentrated under reduced pressure. The resulting residue silica gel column purified by chromatography (chloroform:methanol:95:5) and rediscovered with hexane-ethyl acetate. slurried to give Compound 11 (54.6 mg, 71%) as a pale brown solid. carboxamide (Compound IJ) 60% sodium hydride (in was dissolved, methanol ( ) was added slowly dropwise and the mixture was minutes at 0°C. Then DMF (dissolved in, Example 16, step 2-(chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine- 4-carboxamide (81.0 mg, 0.189 mmol) was slowly added dropwise thereto and the mixture was mixed. hour stirred at room temperature. Mixture of water and a saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. organic layer saturated salt washed with water, dried over anhydrous magnesium sulfate and under reduced pressure concentrated. The resulting residue was purified by silica gel column chromatography (hexanzetyl acetate:50:50) and Compound IJ (45.0 mg, 56%) white by recrystallization from ethanol-water 2-Ethoxymethyl-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridin-4- carboxamide (Compound IK) Obtained as white crystals from ethanol. (brs, 1H). APCIMS m/Z: [M+H]+ 442.

N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-isopropoxymethylpyridine-4- carboxamide (Compound IL) Obtained as white crystals from propanol. 1H NMR (CDC13, kisspm): 1.31 ((1, J : , 1H), 9.91 (brs, 1H). APCIMS m/z: [M+H]+ 456. carboxamide (Compound 1M) mg, dissolved in EDC hydrochloride (173 mg, 0.900) mg, and fur0[2,3-b]pyridine-5- The mixture was added to water-a saturated aqueous sodium hydrogen carbonate solution (1 : 1) and The precipitated solid was collected by filtration and dried. The obtained solid silica gel was obtained by column chromatography. Purified (hexane2ethyl acetate=50250) and recrystallized from ethanol-water for Compound IM (81.2 mg, 43%) was obtained. (d, J : 2.4 Hz, 1H). ESIMS m/z: [M+H]+ 424.

N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-(pyridin-Z-yl)acetamide (Compound Obtained as white crystals from 2-pyridyl acetic acid hydrochloride (196 mg, 1.13 mmol).

N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-methoxypyridin-3- carboxamide (Compound [0) (Reference Example) N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]quinoline-3-carboxamide (Compound obtained as pale yellow crystals from quinoline-3-carboxylic acid (142 mg, 0.820 mmol).

N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-5,6-dimethylpyridine-3- carboxamide (Compound IQ) dimethylpyridine-3-carbonitrile (502 mg, 3.79 mmol) 70% aqueous ethanol (in was suspended, sodium hydroxide (444 mg, 11.1 ininol) was added thereto, and The mixture was mixed by heating under reflux for 3 hours. The mixture was cooled to 0°C with ice and 6 mol/L hydrochloric acid ( was added. The mixture was concentrated under reduced pressure. was obtained and the resulting residue was suspended in chloroforrn-methanol. Inorganic The salt was removed by filtration and the resulting filtrate was concentrated under reduced pressure in 5,-6- dimethylpyridine-3-carboxylic acid (569 mg, 99%) obtained as a pale pink untreated solid 1.7 Hz, 1H). step 2. Example 12, same as step 3, Compound IQ (112 mg, 49%) 1.10 mmol) was obtained as white crystals.

S-Ethyl-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-3-carboxamide (Compound IR) Obtained as white crystals from -ethylnic0tinic acid (128 mg, 0.814 mmol). b]pyridine-3-carboxamide (Compound IS) asama l. Sodium hydride (2.06 g, 51.5 mmol) was dissolved in diethyl ether (40 mL) and methanol (addition) slowly at -5°C. and the mixture was stirred at room temperature for 5 minutes and cooled to 0°C. To this one tetrahydro-4H-pyran-4-one ( mixture slowly added. The mixture was stirred at room temperature for 2 hours and the product obtained was diluted with water. (30 mL) was extracted (aqueous solution A). An aqueous solution of piperidine-acetic acid and 2-cyanoacetamide (4.62 g, 54.9) prepared by mmol) was added to the above-mentioned aqueous solution A and the mixture was refluxed for 4 hours. mixed by heating. Acetic acid ( was added to the mixture and after cooling to 0°C) 2-oxo-1,5,7,8-tetrahydro-ZH-pyrano[4,3-b]pyridine- 3-carbonitri1 (: 2.89 (t, carbonitrile (2.50 g, 14.4 mmol) was dissolved in phosphoryl chloride (20 mL) and the mixture was refluxed for 4 hours. mixed by heating under flow. The mixture was allowed to cool to room temperature and slowly at 0°C. After slowly adding to a saturated aqueous solution of sodium hydrogen carbonate, the mixture extracted with chloroform. The organic layer was washed with saturated brine, anhydrous magnesium dried over sulfate and concentrated under reduced pressure. The resulting residue silica 7.63 (5, 1H). was added and the mixture was stirred by heating under reflux for 4 hours. Mix to room temperature After allowed to cool, it was filtered through Celite and the filtrate was placed under reduced pressure. concentrated. A saturated aqueous sodium hydrogen carbonate solution is added to the resulting residue. and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. in hand The resulting residue was purified by silica gel column chromatography (hexanzetyl acetate:50:50) and 7,8- step 4. Same as Example 24, below, 7,8-dihydro-5H-pyrano[4,3-b]pyridine-3- from carbonitrile (609 mg, 3.80 mmol) as a white solid. step 5. Example 12, same as step 3, Compound IS (178 mg, 74%) from the acid (432 mg, 2.00 mmol) as white crystals. cyclopenta[blpyridine-3-carboxamide (Compound IT) (9mL) and the mixture was heated under reflux for 5 hours. mixed up. The mixture was cooled to 0°C with ice and the precipitated solid was collected by filtration. 6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid hydrochloride (543 mg, 44%) pale obtained as a brown solid. mg, 0.546 mmol) and 6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic obtained above obtained as white crystals from the acid hydrochloride (165 mg, 0.827 mmol).

N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-1H-indole-Z-carboxamide (Compound IU) obtained as pale brown crystals from carboxylic acid (350 mg, 2.17 mmol). 6-Ethyl-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-3-carboxamide (Compound IV) Compound 1E (90.0 mg, 0.220 mmol) obtained in Example 12 is ethanol under an argon atmosphere. (10 mL) to which 10% palladium carbon (10%-Pd/C; contains water) (88.9 mg) is added and the mixture was stirred overnight at room temperature under a hydrogen atmosphere.

The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. Obtained The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=30270) and ethanol- recrystallized from water to obtain Compound IV (70.0 mg, 77%) as white crystals. N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-propylpyridine-3-carboxamide (Compound IW) step 1. Same as Example 12, step lide, methyl 6-(1-pr0penyl)nicotinate (327 mg, mmol) was obtained as a colorless transparent oil. milky white from methyl 6-(1-propenyl)nicotinate (326 mg, 1.84 inmol) obtained above step 3. Same as Example 12, step 3, N-[4-(2-furyl)-5-(tetrahydropyran-4- as obtained. step 4. Same as in Example 29, Compound IW (96.0 mg, 76%) above obtained above N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-(1-propenyl)pyridine-3- from carboxamide (125 mg, 0.296 mmol) as white crystals. b]pyridine-3-carboxamide (Compound IX) 1H NMR (CDC13, kisspm): 3.01 (t, J : , 7.7] Obtained from b]pyridine-3-carbonitrile (1.75 g, 8.31 mmol). from b]pyridine-3-carbonitrile (874 mg, 4.96 mmol). obtained as pale brown crystals from the acid hydrochloride (90.9 mg, 0.392 mmol).

S-Acetyl-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6-methylpyridin-3- carboxamide (Compound IY) step 1. In the same manner as Example 12, step 2, 5-acetyl-6-methylpyridine-3-carboxylic acid Obtained as a yellow solid from acetyl-6-methylpyridine-3-carboxylate (561 mg, 2.71 mmol). 2.0 Hz, 1H). il=ket0n ( dissolved in, this (benzotriazol-1- il0xy)tripyrolidinophosphonium hexafluorophosphate (PyBOP) (262 mg, 0.510 mmol), diisopropylethylamine (DIPEA) ( and 5-acetyl-6-methylpyridine-3-carboxylic acid (93.2 mg, 0.520 mmol) was added and the mixture was stirred overnight at 80°C. Mixture allowed to cool to room temperature, followed by water and a saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. organic layer saturated salt washed with water and dried over anhydrous magnesium sulfate. Solvent reduced pressure was evaporated under and the residue obtained by silica gel column chromatography (hexanzet acetate=50:50) was purified and reslurried from ethanol-water to Compound IY (87.4 mg, 77%) as a pale yellow solid.

-Ethyl-N-[4-(3-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-3-carboxamide (Compound IZ) N-[4-(3-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-6,7-dihydro-5H- cyclopenta[b]pyridine-3-carboxamide (Compound IAA)

Claims (12)

REQUESTS 1. A thiazole derivative or a pharmaceutically acceptable salt thereof, represented by formula (IC) for use in the treatment and/or prophylaxis of a movement disorder, wherein the end-dose phenoin seen on administration of movement disorder, L-DOPA and/or dopamine agonist therapy and on-off ripple. 2. The thiazole derivative of claim 1 or a pharmaceutically acceptable salt thereof, wherein the motor complication is the end-of-dose phenomenon. 3. The thiazole derivative of claim 1, or a pharmaceutically acceptable salt thereof, where the motor complication is on-off fluctuation. 4. The thiazole derivative S melis or a pharmaceutically acceptable salt thereof, represented by formula (IC) for use in suppressing or reducing a movement disorder, wherein the movement disorder is the end-of-dose phenomenon upon administration of L-DOPA and/or dopamine agonist therapy. and on-off ripple. 5. The thiazole derivative of claim 47 or a pharmaceutically acceptable salt thereof, wherein the motor complication is the end-of-dose phenomenon. 6. The thiazole derivative of claim 4, or a pharmaceutically acceptable salt thereof, where the motor complication is on-off surge. 7. Use of a thiazole derivative represented by formula (IC), or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for the treatment and/or prophylaxis of a movement disorder, wherein the movement disorder is administered with L-DOPA and/or dopamine agonist therapy It is a motor complication selected from the end-of-dose phenomenon and the on-off fluctuation seen on 8. Use according to claim 7, wherein the motor complication is the end-of-dose phenomenon. 9. Use according to claim 79, wherein the motor complication is on-off surge. 10. The use of a thiazole derivative represented by formula (IC), or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for suppressing or reducing a movement disorder, wherein the movement disorder is seen upon administration of L-DOPA and/or dopamine agonist therapy. It is a motor complication chosen between the end-of-dose phenomenon and the on-off fluctuation. 11. The use according to claim 10,21 wherein the motor complication is the end-of-dose phenomenon. 12. Use according to claim 10,21 wherein the motor complication is on-off surge.